Male 11ß-HSD1 Knockout Mice Fed Trans-Fats and Fructose Are Not Protected From Metabolic Syndrome or Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) defines a spectrum of conditions from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis and is regarded as the hepatic manifestation of the metabolic syndrome. Glucocorticoids can promote steatosis by stimulating lipolysis within adipose tissue, free fatty acid delivery to liver and hepatic de novo lipogenesis. Glucocorticoids can be reactivated in liver through 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) enzyme activity. Inhibition of 11ß-HSD1 has been suggested as a potential treatment for NAFLD. To test this, male mice with global (11ß-HSD1 knockout [KO]) and liver-specific (LKO) 11ß-HSD1 loss of function were fed the American Lifestyle Induced Obesity Syndrome (ALIOS) diet, known to recapitulate the spectrum of NAFLD, and metabolic and liver phenotypes assessed. Body weight, muscle and adipose tissue masses, and parameters of glucose homeostasis showed that 11ß-HSD1KO and LKO mice were not protected from systemic metabolic disease. Evaluation of hepatic histology, triglyceride content, and blinded NAFLD activity score assessment indicated that levels of steatosis were similar between 11ß-HSD1KO, LKO, and control mice. Unexpectedly, histological analysis revealed significantly increased levels of immune foci present in livers of 11ß-HSD1KO but not LKO or control mice, suggestive of a transition to NASH. This was endorsed by elevated hepatic expression of key immune cell and inflammatory markers. These data indicate that 11ß-HSD1-deficient mice are not protected from metabolic disease or hepatosteatosis in the face of a NAFLD-inducing diet. However, global deficiency of 11ß-HSD1 did increase markers of hepatic inflammation and suggests a critical role for 11ß-HSD1 in restraining the transition to NASH.

Regulation of lipid metabolism by glucocorticoids and 11ß-HSD1 in skeletal muscle.

The prevalences of insulin resistance and type 2 diabetes mellitus are rising dramatically, and, as a consequence, there is an urgent need to understand the pathogenesis underpinning these conditions to develop new and more efficacious treatments. We have tested the hypothesis that glucocorticoid (GC)-mediated changes in insulin sensitivity may be associated with changes in lipid flux. Furthermore, prereceptor modulation of GC availability by 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) may represent a critical regulatory step. Dexamethasone (DEX) decreased lipogenesis in both murine C2C12 and human LHC-NM2 myotubes. Inactivating p-Ser-79/218 of acetyl-CoA carboxylase 1/2 and activating p-Thr-172 of AMP-activated protein kinase were both increased after DEX treatment in C2C12 myotubes. In contrast, DEX increased ß-oxidation. Selective 11ß-HSD1 inhibition blocked the 11-dehydrocorticosterone (11DHC)-mediated decrease in lipogenic gene expression and increase in lipolytic gene expression. Lipogenic gene expression was decreased, whereas lipolytic and ß-oxidative gene expression increased in corticosterone (CORT)- and 11DHC-treated wild-type mice and CORT (but not 11DHC)-treated 11ß-HSD1(-/-) mice. Furthermore, CORT- and 11DHC-treated wild-type mice and CORT (but not 11DHC)-treated 11ß-HSD1(-/-) mice had increased p-Ser-79/218 acetyl-CoA carboxylase 1/2, p-Thr-172 AMP-activated protein kinase and intramyocellular diacylglyceride content. In summary, we have shown that GCs have potent actions on intramyocellular lipid homeostasis by decreasing lipid storage, increasing lipid mobilization and utilization, and increasing diacylglyceride content. It is plausible that dysregulated intramyocellular lipid metabolism may underpin GC-induced insulin resistance of skeletal muscle.

Biomarkers of hypothalamic-pituitary-adrenal axis activity in mice lacking 11ß-HSD1 and H6PDH.

Glucocorticoid concentrations are a balance between production under the negative feedback control and diurnal rhythm of the hypothalamic-pituitary-adrenal (HPA) axis and peripheral metabolism, for example by the enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), which catalyses the reduction of inactive cortisone (11-dehydrocorticosterone (11-DHC) in mice) to cortisol (corticosterone in mice). Reductase activity is conferred upon 11ß-HSD1 by hexose-6-phosphate dehydrogenase (H6PDH). 11ß-HSD1 is implicated in the development of obesity, and selective 11ß-HSD1 inhibitors are currently under development. We sought to address the concern regarding potential up-regulation of the HPA axis associated with inhibition of 11ß-HSD1. We assessed biomarkers for allele combinations of 11ß-HSD1 and H6PDH derived from double heterozygous mouse crosses. H6PDH knock out (KO) adrenals were 69% larger than WT while 11ß-HSD1 KO and double KO (DKO) adrenals were ~30% larger than WT - indicative of increased HPA axis drive in KO animals. ACTH-stimulated circulating corticosterone concentrations were 2.2-fold higher in H6PDH KO animals and ~1.5-fold higher in 11ß-HSD1 KO and DKO animals compared with WT, proportional to the observed adrenal hypertrophy. KO of H6PDH resulted in a substantial increase in urinary DHC metabolites in males (65%) and females (61%). KO of 11ß-HSD1 alone or in combination with H6PDH led to significant increases (36 and 42% respectively) in urinary DHC metabolites in females only. Intermediate 11ß-HSD1/H6PDH heterozygotes maintained a normal HPA axis. Urinary steroid metabolite profile by gas chromatography/mass spectrometry as a biomarker assay may be beneficial in assaying HPA axis status clinically in cases of congenital and acquired 11ß-HSD1/H6PDH deficiency.